ABSTRACT Microglia,-the resident macrophages of the central nervous system (CNS), are thought to be important contributors to CNS health and' disease but their exact functional roles are still mysterious. Direct CNS damage, as well as peripheral injuries and addictive drug exposure, all induce microglial activation. A longstanding limitation in investigating microglia is the lack of good tools to distinguish and manipulate microglia specifically without altering macrophages or other immune cell types. In this proposal we will use new tools that our lab has recently generated to specifically identify and genetically manipulate microglia in order to investigate their function. First we will use these tools to develop the first in vitro culture system in which purified microglial cells can be cultured in defined serum-free medium with high survival in a non- activated state. This will enable us to directly test their specific functions for the first time including their ability to promote neuronal and glial survival, or to regulate synapse formation and function, as well as to elucidate the specific signals that induce their activation and to assess how their normal functions are altered when microglia become activated. Second, we will perform metabolomics analysis to investigate nature of the chemical signaling molecules that resting and activated microglial cells secrete. Third, we will use the new genetic tools we have developed to ablate microglia to elucidate their role in the establishment and maintenance of reactive gliosis! and neuropathic pain. Lastly vye will identify the specific molecular mechanisms through which microglial cells influence these processes. Presently, drugs available for treatment of pain, such as opiates, suffer from undesired side effects and the development of tolerance. The purpose of the proposed research is to determine the molecular events that produce glial cell mediated neural circuitry modifications, opioid tolerance and addiction, as well as neuropathic pain in order to identify novel therapeutic targets. The findings will lay the groundwork for future research in understanding the role of microglia in drug- induced plasticity in reward-related neuronal circuits. Principal Investigator/Program Director (Last, First, Middle): Barres, Ben A. BIOGRAPHICAL SKETCH Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2. Follow this format for each person. DO NOT EXCEED FOUR PAGES. NAME POSITION TITLE Barres, Ben A. Professor of Neurobiology eRA COMMONS USER NAME BARRES.BEN EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.) DEGREE INSTITUTION AND LOCATION YEAR(s) FIELD OF STUDY (ifapplicable) Massachusetts Institute of Technology SB 1976 Life Science Dartmouth Medical School M.D. 1979 Medicine Harvard Medical School Ph.D. 1990 Neurobiology University College London Postdoc 1993 Neurobiology A. Personal Statement Over the past 20 years, my lab has focused on the role of neuron-glial interactions In the CNS. As I am trained In clinical neurology, I am greatly Interested in understanding the pathophysiology of CNS injury and disease processes and how to enhance repair and regeneration. I believe that my lab is an appropriate training environment for young scientists. I have been doing research on glial cells for 30 years and so have much experience and knowledge concerning glial cells. I have mentored a number of talented young scientists who are now running their own labs in academic institutions (including Erik Ullian at UCSF, Jeff Goldberg at U. Miami, Cagia Eroglu at Duke University, Ben Emery at U. Melbourne, Andrew Huberman at UCSD, Beth Stevens at Harvard/Childrens Hospital Boston, and Nicola Allen at Salk institute). B. Position and Honors Employment/Experience 1980-1983 Chief Resident, Resident in Neurology, Cornell Cooperating Hospitals 1979-1980 Internship in Internal Medicine, Cornell Cooperating Hospitals 1993-1997 Assistant Professor of Neurobiology, Stanford University School of Medicine 1997-2001 Associate Professor of Neurobiology and Dev. Biology, Stanford Univ. School of Medicine 1998-2008 Associate Chair, Department of Neurobiology, Stanford University School of Medicine 2001-2005 Co-Director, Neuroscience Institute at Stanford 2001- Professor of Neurobiology, Dev. Biology, and Neurology, Stanford Univ. School of Medicine 2003- Team Member, Myelin Repair Foundation 2005- Executive Committee, Neuroscience Institute at Stanford 2005- Director, Masters of Science in Medicine Degree Program for PhD Students at Stanford Univ. 2008- Chair, Department of Neurobiology, Stanford University School of Medicine 2009-2010 Member, Stanford University Advisory Board Honors 2012 Fellow, American Academy of Arts and Sciences 2011 Fellow, American Association for the Advancement of Science 2010 Alcon Research Institute Vision Award 2008 Mika Salpeter Lifetime Achievement Award, Society of Neuroscience 1999, 03, 07 Kaiser Award for Excellence in Preclinical Teaching 1997 Kaiser Award for Outstanding Contributions to Medical Education 1997-2001 McKnight Investigator Award 1995 Kaiser Award for Excellence in Preclinical Teaching 1993-1996 Searle Scholar Award; McKnight Scholar Award, Klingenstein Fellowship Award 1989-1992 Life Sciences Research Fellowship; National Multiple Sclerosis Society Fellowship 1980, 1984 Diplomate, Am. Board of Psych, and Neurology, and National Board of Medical Examiners 1976 Bell Labs Engineering Scholar PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 1 Biographical Sketch Format Page